Halogenated derivatives of aceto propane



Patented Nov. 24-, 1942 UNITED STATES PATENT OFFICE-l HALooENATEnDERIVATIVES 0F AoETo PROPANE Edwin R. Buchnian, Pasadena, Calif.,assign'or to Research Corporation, New York, N. Y., a cor poration ofNew York No Drawing; Original application September2l,

1939, Serial No. 296,817.

Divided and this 'ap plication August 21, 1940, Serial No. 353,505 6Claims. (01. zoo-e45) This invention relates to the production ofhalogenated derivatives of aceto propane and has for its object theprovision of new and useful de'-' rivativ'es of this nature and usefuland effective methods-of making-them. I-Ialogenated derivatives ofthe-type-to which this invention relates are useful in the synthesis ofvitamin B1, which has extremely valuable therapeutic and nutritionalproperties.

This application'is a division of my copendin'g application Serial No.296,817 filed September 27,

1939, for Halogenated derivatives of 'aceto propane, which in turn wasfiled as a continuation in part of my applications, Serial Nof118,5 '73,filed December 31, 1936, and Serial No. 171,905,

filed October '30, 1937. Application Serial No; 118,573 was'a divisionof application Serial No. 98,929; which I filed September 1, 1936, whileapplication Serial No.171,'905 was a continuation in part of applicationSerial No. 11,683, which I filed March 18, 1935, and of said applicationSerial In the'foregoing'applications the product obtained'byhalogena'tingv aceto propyl alcohol or by hydrolysing halogenated aaceto y butyrolactone is describedas 'y halogen aceto propyl alcohol butit has been subsequently found that molecules of a 'y halogen 'y acetopropyl alcohol tend to react spontaneously with one another toform"'halogenated a'oeto propyl others with 'sur-.

prising LeaseJ These ethers when in aqueous solutions hydrolyze into thehalogenated alcohol more or less completely according to theconcentration and temperature. When 'y halogen 'y aceto propyl alcoholis distilled, the resulting product may consist predominately of eitherthe'alcohol or the ether depending upon the temperature, pressure and/orspeed of the distillation. The conditions for isolation described in theabove mentioned applications are such as to produce,

in whole or in part, the ether rather than the alcohol.

There are threepossible forms in which 7 aceto propyl alcohol mayexistQthe formulae of which may be written:

(ketonic form) II (enelic form) and In (innerether, lactone, ortehahydroiurane form) It is probablethat any solution'of this productcontains some orall'of these "formsin equilib-"- rium. The aboveoutlined ketonic'iorm undoubtedly is in tautomeric equilibrium with theenolic" These; tautomertic' forms form of the molecule. are, however, soreadily mony with enolketo" inter'convertible', in 'har-j ignored in"th'following discussion.

The sveialhaldgen derivatives of 'y' aceto pro:

pyl alcohol? likewise may exist in similar forms having the structures:

O i V mo' -on'it onkcmon in which X one'o'f the' halogens chlorine," bromine anaiod ueig v It is Obvious that'When'tWo moleculso'f one of thesehalogenated aceto'pi'opyl alcohols react 'aneth'e'r; the-resultingether'inay have" to form I any one ofthe fonowinjg structures?QHs--CO-CHX-CI-Iz-CHz o-oHz-' cHzoHX-co-cH3 VI c113 3111 onko-o-o-C-O-omcuterm orix ong v vn' and,: 1

' ona oo cnx onz oru o-o oon, onir om VIII in which formulae, X hasthesame-significance as befo'reL It is difiiciilt'to determine which ofthe'sjef'forr'ns "the "ether will assume under any givensetofconditionsfbut'it appears that the form usuauy obtained underordinaryconditions, as in the specific examples'giveii hereinafter, possess'es'one tetraliydrofuraneradical and-has the "structure indicated by FormulaVII Il v In the :aforementioned application Serial No. 171,905/1 havedescribed several methods of making' halogenfderivatives of 7 acetopropyl-alcohol 'ahd' have described the properties of the resultingproducts. sev'eral products of reaction" which'boil'over the range from'84 to 120 C. at

1 to 2 mmQpressure are described therein and,

while halogen derivatives of 'y aceto propylalcohol undoubtedlyare-present-in the reaction mix--' tures obtained by halogenation of vaceto propyl I tamorhrsm general, that for the sake of simplicity theenolic forms will be alcohol, one of the above described halogenatedethers is the principal product obtained upon distillation under'theconditions described, instead of the corresponding halogenated alcoholas stated in my previous applications referred to hereinabove. However,for all practical purposes, the desired result is obtained no matterwhich compound is secured because in the presence of traces of Water theether reacts as if the alcohol were used. For example, if the product isdissolved in water, a solution containing halogenated aceto propylalcohol is obtained. Since the principal intended use of the product isin the synthesis of the thiazole portion of vitamin B1 and in suchsynthesis Water is present or is formed in the course of the reaction,the particular product isolated is more or less immaterial except from atheoretical standpoint. Because the ether is more stable than thealcohol, it is preferable from a practical standpoint to employ theether.

In accordance with the present invention, a halogenated derivative ofaceto propane may be prepared by the halogenation of 'y aceto propylalcohol with one of the elemental halogens bromine, chlorine and iodineor with sulphuryl bromide or sulphuryl chloride. The same halogenatedderivative may likewise be made by halogenating a aceto v butyro lactonewith the same halogenating agent and then subjecting the resulting ahalogenated butyrolactone to a combined hydrolysis and decarboxylation.The reaction product is then treated in a suitable manner to remove thedesired product, or products, which may be a halogen derivative of 'yaceto propyl alcohol, a halogen derivative of aceto propyl ether, orboth, depending upon the isolation process.

The invention will be fully understood from the following detaileddescription of specific embodiments thereof. As an example of how theinvention may be practiced, 'y aceto propyl alcohol maybe halogenated bytreatment with a suitable halogenating agent, such as a halogen or asulfuryl halide.

Example 1 In accordance with one specific embodiment of the invention, 7brom 'y aceto propyl alcohol, which may also be designated3-brom-3-acetopropan-l-ol, may be prepared by dissolving grams of 7aceto propyl alcohol in 150 cc. of water and vigorously stirring thesolution while 48 grams of bromine are added drop by drop at such a ratethat the color imparted to the solution by one drop of the brominedisappears before the next drop is added. The aqueous solution whichresults contains impure 'y brom v aceto propyl alcohol.

One method of purifying the product is to separate the small amount ofinsoluble oil which is formed as a by-product, from the aqueous solutionand to extract the aqueous solution repeatedly with ordinary ethyl etherto dissolve the remainder of the brominated product. The insoluble oiland the ethereal extracts are combined and dried over a suitabledehydrating agent such as anhydrous sodium sulphate. The ethyl ether isthen distilled ofi and the residue is practically pure di (bromo acetopropyl) ether which is hereinafter designated from aceto propyl ether.This material may be further purified, if desired, by distilling it invacuo at less than 1 mm. of mercury. The product is a colorless oil,which is soluble in hot water, ether and alcohol and which may bedistilled though not without some decomposition. The pure substance canbe readily distilled in a molecular still at 40 C. bath temperature andat 0.008 mm. pressure. Calcd. for: CwHrsOsBrz, mol. Wt.=343.96;

0:34.89; H=4.69. Found: mol. wt.=316 (di oxane); C=34.84; H-=4.56. d=1.592 gm./cc'.- n =1.4989.

The brom aceto propyl ether thus prepared is sparingly soluble in Waterbut freely soluble in organic solvents such as petroleum ether. It maybe converted into '7 brom 'y aceto propyl alcohol by making a dilutewater solution thereof, for it hydrolizes readily into the brominatedalcohol. The solution of the ether in water may be most readily efiectedby mild heating at a temperature of 50 to 60 C. The brom alcohol has notbeen isolated as such because it goes over into the ether too readily.However, the presence of the alcohol in a water solution of the bromether has been established by freezing point depression of the aqueoussolution.

Eztample 2 The corresponding chlorine derivatives may likewise be madeby direct reaction of chlorine upon 7 aceto propyl alcohol. Thisreaction may be carried out by treating 12 grams of 'y aceto propylalcohol, dissolved in 60 cc. of water, with a stream of gaseouschlorine, the reaction mixture being stirred and cooled if necessary sothat the temperature remains between 20 C. and 40 C. This is continueduntil the increase in weight of the reaction mixture reaches 8 grams.The mixture is cooled to about 15 C. and allowed to stand 15 minutesduring which time a small, heavy, oily layer separates at the bottom ofthe vessel. This oily layer is removed and washed twice with water. Theaqueous layer and the aqueous washings are extracted with ethyl ether.Then the ethereal extracts are combined with the above oily layer anddried over a suitable dehydrating agent, such as sodium sulfate. Theethyl ether is evaporated off leaving an oil boiling at 87 C. to C. atabout 2 mm. pressure, This material is a stable, colorless oil which issoluble in ether, alcohol and hot water and is slightly soluble in coldwater. This product consists principally of chlor aceto propyl etherhaving the properties described in Example 5 below.

The invention also contemplates the production of the related iodinederivatives in a similar manner, although iodine is not so reactive asbromine or chlorine and the yield of the iodine compounds is not sogreat.

Instead of using halogens as the halogenating agents, sulfuryl halides,such as sulfuryl chloride or sulfuryl bromide may be employed.

Example 3 In practicing one process of this nature, 27 grams of sulfurylchloride are added slowly to 20.4 grams of v aceto propyl alcohol andthe reaction mixture is kept at 0 C. for one-half hour. At the end ofthat time, 50 added and the mixture is heated to expel the sulfurdioxide and the hydrogen chloride remaining in the mixture. The mixtureis then cooled and poured onto crushed ice and the excess acidity isneutralized with a potassium carbonate solution. The resulting mixtureis repeatedly extracted with petroleum ether and the ether extract istreated first with anhydrous sodium sulfate and finally with anhydrouspotassium carbonate. After the extract is dried,

the residue is distilled in vacuo to remove the petroleum ether v andthe residue is fractionally distilled .vacuo, whereupon a product havina boiling point at;2 mm. pressure of about 90 to 120 C, is obtained.This product also consists predominantly of the aforementioned chloraceto propyl ether.

The corresponding brom compounds may be prepared in a similar manner byreacting upon 7 aceto propyl alcohol with an equivalent amount ofsulfuryl bromide and purifying the product obtained by a similarprocedure.

The brom, chlor and iodo derivatives of aceto propane describedhereinbefore may also be made by simultaneously hydrolizing anddecarboxylating the corresponding a halogen derivative of 0c aceto vbutyro lactone. The a aceto 'y butyrolactone employed in this reactionhas the formula ,dium ethylate or sodium methylate, the latter beingpreferred.

Example 4 Chlor aceto propyl ether may be obtained by first preparing achlor oz aceto 'y butyro lactone by treating on aceto v butyro lactonewith sulfuryl chloride, in accordance with the method described in myaforesaid application Serial No. 118,573, now Patent No. 2,193,858,issued March 19, 1940.

In carrying out this reaction 68 grams of the a aceto 'y butyrolactoneare placed in a flask equipped with a mechanical stirrer and 68 grams ofsulfuryl chloride are added with continual stirring over a period of oneand a half hours. After the reaction is completed the reaction productis washed with water, taken up in ether and dried over a suitabledehydrating agent, such as calcium chloride. distilled at a reducedpressure and the fraction distilling at approximately 85 C. and 2 or 3mm. pressure is collected. This product is substantially pure or chlor aaceto v butyrolactone having the formula:

CHsO O OHClCHaCHzOH-l-fi 02 A similar result is obt'ained by using-adilute The etheral extract is then 3 Found:

solutionbf' an alkaliinstead of the dilute acid. The acid and allgaliare both examples of pH modifying agents.

The reaction mixture is then extracted several times with small-portionsof ethyl ether and the combined ethereal solution is driedover adehydrating material, such .as sodium sulphate. The dried solution isthen distilled in vacuo and the portion boiling at to C. at 2 to 3 mm.pressure is, collected. The collected material is principally chloraceto propyl ether and is substantially identical with the productobtained by direct chlorination of 'y aceto propyl alcohol anddistillation of the reaction product as described in Example 2.

Example 5 410 grams of the chlorinated lactone prepared as described inExample 4 are heated on a steam bath with 410 cc. of water and 12 cc. of38% hydrochloric acid until decarboxylation is complete. This operationrequires about 7 hours. On cool ing the reaction mixture an oily layerseparates which is removed by repeated extraction of the mixture withpetroleum-ether. The ether extracts are then shaken with solid potassiumcarbonate and 01:27.81. Found: mol. wt. 259 (dioxane);

(3:47.13; .H:6.13; and ,Cl:28.07. d -1.2175 gm./cc.; n :l.4748. Thischlor aceto propyl ether is a colorless and almost odorless liquid whichis soluble withdifliculty in water but which is readily soluble inorganic solvents.

Example 6 If the only liquid described in Example 5 is fractionallydistilled at 1.7 mm. pressure and that fraction which is obtained at 68to 70 C. is redistilled at 3 10 mm. at 20 to 24 (3., a fraction isobtained consisting of 'y chlor y aceto propyl alcohol. Calcd forCal-190201; mol. Wt.:136.54; (3:43.95; 11:6.64; and Cl:25.96. mol.wt.:l46 (dioxane); 0:44.64; 11:62.9 and 01:26.43. d-"*:1.210 gm./cc.; n:1.4684. This chlor aceto propyl alcohol is insoluble in petroleumether, whereas the chlor aceto propyl ether is soluble therein.

If, however, this low boiling fraction 1s redistilled at 1.7 mm.pressure, most of the distillate boils in the ether range, that is aboutC. with splitting off of water, which can be collected in a carbondioxide trap. Thus, it is evident that both chlor aceto propyl alcoholand chlor aceto propyl ether may be obtained from the same reactionmixture and that the product isolated depends upon the conditions whichexist during the isolation step.

Aqueous solutions of chlor aceto propyl ether give molecular weightvalues indicating complete hydrolysis into chlor aceto propyl alcohol.The ether goes into Water solution readily when the mixtures are warmed,60 C. having proved to be a satisfactory temperature to employ.

Example 7 with500 cc.- of water at 60C: for-about six hours and themixture is allowed to stand. All of the resulting oily layer willdissolve upon shaking the mixture. The mixture is extracted repeatedlywith ether, the ethereal extracts are dried over a suitable dehydratingagent, such as sodium sulfate, and the solvent is then removed in awater pump at 200 C, The residual oil is then fractionally distilled ina molecular still and 'y chlor aceto propyl alcohol, boiling at 27 C. at0.01 mm. pressure is obtained. Calcd for CH902C12 mol. wt.=136.54;0:43.95; II=6.64, and 01:25.97. Found: apparent mol. wt.=1l8.5 correctedfor mol. of Water consumed in the hydrolysis would give mol. wt.=127.5;0:44.35; H=6.48. d =1.210 gm./cc. n D=l.4684. The chlor aceto propylalcohol is insoluble in petroleum ether, while chlor aceto propyl etherdissolves therein readily.

The bromine compound which corresponds to the chlorinated lactonedescribed hereinabove in Example 4 may be made in an analogous manner bytreating a aceto 'y butyrolactone with sulphuryl-bromide or in aqueoussuspension with bromine. The bromide compound corresponding to the abovedescribed chlorinated aceto propyl alcohol may then be prepared bytreating the brominated lacetone with a suitable pI-I regulating agent,such as dilute hydrobromic acid.

Example 8 These reactions may be carried out by suspending 32 grams of aaceto 'y butyrolactone in '70 cc. of water and adding 40 grams ofbromine thereto drop by drop, meanwhile vigorously stirring the mixturewith a mechanical stirrer. This will produce a bromo a aceto 'ybutyr'olactone and in the reaction which occurs hydrobromic acid is alsoproduced. This brominated lactone may be hydrolyzed and decarboxylatedby means of a dilute solution of hydrobromic acid. Since hydrobromicacid is present in the reaction mixture resulting from the brominationoi the lactone, the simplest way to hydrolyze the brominated lactone isto continue to stir the mixture after the bromine has been added, untilthe hydrolysis and decarboxylation are completed. The brominated productresulting from the hydrolysis is extracted from the mixture with ether,and the ethereal extract is dried. The dried extract is freed from ethylether and is then distilled in vacuo at about 1 mm. pressure and thebrom aceto propyl ether is collected. This material is an oil which iscolorless when freshly made, but it is not as stable as thecorresponding chlorine compound and darkens on standing,

The corresponding 7 iodo 'y aceto propyl alcohol and iodo aceto propylether may be produced in smaller yields than the related chlor and bromcompounds by employing elemental iodine instead of the chlorinating andbrominating agents mentioned previously in the several reactionsdescribed hereinabove. If desired, the iodo compounds may also beprepared in more substantial yields, by treating one of the chlor orbrom alcohols or ethers with sodium iodide.

As stated previously, the halogenated aceto propyl ethers obtained mayassume the structures indicated by Formulae VI, VII, and VIII outlinedhereinabove. If VI were the correct structure, one would expect that twomolecules of phenyl hydrazine would react with 1 molecule of thedi-halo-aceto-propyl ether. If the correct structure were VII phenylhydrazine would not react with this ether at all. Actually, in fullagreement with structure VIII, only 1 molecule of phenyl hydrazinereacts with 1 molecule of the ether. When a second molecule of phenylhydrazine is present, it separates from the reaction mixture as phenylhydrazine hydrochloride. The product of reaction of phenyl hydrazinewith v halogen 'y aceto propyl ether is analogous in structure to"tetraphenyltetracarbazon described by Sven Bodforss in Berichte derdeutschen chemischen Gesellschaft, vol. 52, p. 1762 and 1767 (1919) andV0]. 72, p. 468 (1939). The reaction involved is also analogous to thatof Bodforss, but only one side of the molecule undergoes reaction withphenyl hydrazine. Thus the product of the action of phenyl hydrazine on'y chloro 'y aceto propyl ether having the properties described inExample 5 is a yellowish crystalline powder melting at about C.,insoluble in water or petroleum ether, but soluble in other usualorganic solvents, such as alcohol, acetone or ether. It has acomposition corresponding to the formula C16H2102N2C1 According to thelater ideas of Bodforss, its structure is as follows:

If an excess of phenyl hydrazine is used in the above reaction and aninert solvent is employed, the excess of the reagent is unchangedshowing the presence of one and only one a chlor keto group in themolecule of the 'y chloro 'y aceto propyl ether. This is furtherconfirmed by the action of iodine on an aqueous alkaline solution of 'ychloro 'y aceto propyl ether. If this reaction is carried out with acold water solution only half as much iodine is consumed as is the casewhen the 'y chloro 'y aceto propyl ether is first warmed with water fora few minutes before carrying out the iodine reaction. This is evidencethat the ether has only one COCH3 group and that another such group isformed when the ether is hydrolyzed into the related alcohol.

From the foregoing, it is apparent that the halogenated aceto propylethers produced as described hereinbefore contain at least onetetrahydrofurane group and that in all probability they contain only onesuch group. However, the appended claims are intended to embrace allforms of the ether unless specifically limited to cover only certainones of such ethers.

The chlorine, bromine and iodine derivatives of 'y aceto propyl alcoholand ether produced in accordance with the invention may be condensedwith thio formamide to produce salts of the thiazole derivative known as4-methyl-5-(fihydroxy-ethyl) thiazole in accordance with the methodoutlined in Patent No. 2,133,966 granted October 25, 1938. This thiazolederivative may in turn be caused to enter into other reactions toproduce synthethic compounds having the characteristic physiological andtherapeutic properties of the antineuritic vitamin.

What is claimed is:

1. The process of converting a 'y halogen 1 aceto propyl alcohol intothe corresponding ether which comprises dehydrating the alcohol.

2. The process of converting a 7 halogen '7 aceto propyl alcohol intothe corresponding ether which comprises distilling the alcohol underreduced pressure.

3. The chemical compound diby-halogen-yaceto'propyl) ether wherein thehalogen is a member of the group consisting of bromine, chlorine andiodine,

4. A chemical compound having the formula Rr-O'R in which R and R aregroups of the class consisting of CHaCOCHXCI-IzCHzand wherein X is oneof the halogenes bromine, chlorine and iodine.

5. A chemical compound having the formula R-O-R' in which R. and R aregroups of the class consisting of CH3COCHXCH2CH2 and wherein X is one ofthe halogens bromine, chlorine and iodine, and in which at least one ofthe groups represented by R and R is CH; oni-o- CH2-CHX 6. The compoundhaving the formula,

on, mire OCHXCHT- 0H,- 0- 0-011, CHIC-CH, EDWIN R. BUCHMAN.

